Novel 6-fluoro-delta6-steroids and processes



3,359,288 NGVEL 6-FLUORO-A -STERIDS AND PROCESSES Meyer Sletzinger, North Plainfield, N.J., assignor to Merck & (30., inc, Railway, N..li., a corporation ed New Jersey No Drawing, Filed Mar. 13, I961, Ser. No. 95,006

7 Claims. (Cl. 26039'7.45)

It is further concerned with the processes and intermediate porducts used to prepare such compounds.

This application is a continuation-in-part of co-pending application Ser. No. 746,661 filed July 7, 1958.

The steroid substances defined by this general formula, where R is hydrogen, hydroxy, or acyloXy, R is a hydroxy or keto group, X is hydrogen or fluorine and the dotted line between the C1-C2, carbon atom signifies a single or a double bond, have an unusually high degree of anti-inflammatory activity without the undesirable side efiects associated with anti-inflammatory steroids commercially available at the present time.

It is an object of the invention to provide such 60t-flllOI'O- 16-methyl steroid compounds. It is also an object to provide methods for making them and to provide other new steroids which are useful as intermediates in such syntheses. These and other objects will be apparent from the following discussion:

The process of the invention comprises dehydrogenating l7oc,2l-dihydroxy-6-fluoro-16-methyl-11 oxygenated- 4-pregnene-3,20-dione 21-esters, 170:,21 dihydroxy 6- fiuoro-l6-methyl-1l-oXygenated-4,6 pregnadiene 3,20- dione 21-esters, and 9-halo derivatives thereof, to produce the 4,6-pregnadiene and 1,4,6-pregnatriene ZI-esters respectively, thereafter converting these compounds to their 21-desoxy derivatives. The dehydrogenation of the 17u,21- dihydroxy-6-fluoro-l6-methyl-11-0xygenated-4 pregnene- 3,20-dione starting material is accomplished by treating a 17a,21-dihydroxy-6-fluoro-16-methyl-11 oxygenated 4- pregnene-3,20-dione 21-ester with chloranil, to obtain the corresponding 170:,2l-dihydroxy-6-fluoro-16-methyl 11- oxygenated-4,6-pregnadiene-3,ZO-dione 2l-ester. The dehydrogenation of the thus-obtained 4,6-pregnadiene is accomplished with selenium dioxide to yield the 1l-oxy genated-17a,21-dihydroxy-6-fluoro-16-methy1-1,4,6 pregnatriene-3,20-dione 21-ester. These 2l-esters are subjected to mild alkaline hydrolysis to form the 21-free alcohols, and are reacted with a lower alkane sulfonyl halide thereby forming the 2l-lower alkane sulfonate of 17u,21-dihydroxy-6-fiuoro-16-rnethyl-1 1-oxygenated-4,6-pregnadiene- 3,20-diones and 17a,21-dihydroxy-6-fiuoro-16-methyl-11- oxygenated-l,4,6-pregnatriene-3,20 diones, and 9 halo derivatives thereof; these 21-Iower alkane sulfonate com pounds are reacted with an alkali metal iodide thereby forming 2l-iodo-17a-hydroxy-6-fluoro-16-methyl-11 oxygenated-4,6-pregnadiene-3,20-diones, 2l-iodo 17cc 11ydroxy-6-fluoro-16-methyl-1l-oxygenated 1,4,6 pregnatriene-3,20-diones, and 9-halo derivatives thereof, which upon reaction with a reducing agent are converted to the corresponding 17oc-hydroxy-6-fluoro-16-methyl-11 oxygenated-4,6pregnadiene-3,20-diones, 17a hydroxy 6- fluoro-l6-methyl-l l-oxygenated-1,4,6-pregnatriene 3,20- diones, and 9-h-alo derivatives thereof.

The chloranil dehydrogenation of this invention is conducted using the 21-ester of the starting material to prevent extensive degradation of the dihydroxy-acetone side chain. The reaction is conveniently carried out by bringing the reactants together in a solvent medium such as a lower alkanoyl ester, alcohols, organic acids or mixtures of esters and acids. Typical examples of such solvents are ethyl acetate, propyl acetate, ethyl alcohol, t-butyl alcohol, acetic acid or mixtures of ethyl acetate and acetic acid, and the like. In one method for producing the compounds of our invention the ZI-acetate of 11/3,17a,21-trihydroxy- 6a-fluoro-l6a-methyl-4-pregnene-3,ZO-dione is suspended in ethyl acetate and acetic acid and mixed with approximately twice its weight of chloranil. The suspension is heated at the reflux temperature under nitrogen for a period of from about 15 to 20 hours to form the corresponding 21-acetate of 11/8,l7a,2l-trihydroxy-6-fluoro 16ccmethyl-4,6-pregnadiene-3,20-dione. The resulting product is conveniently recovered by extraction with an organic solvent followed by chromatography over activated alumina.

In similar manner, the 21-acetate of the corresponding ll-keto compound, 1711,21-dihydroxy-6a-fiuoro-l6amethyl-4-pregnene-3,l1,20-trione 21-acetate is converted to 17oc,2l-dihydroxy-6-fluoro-16u-rnethyl-4,6-pregnadiene- 3,11,20-trione 21-acetate. In an alternate method of preparing the ll-keto-compound the corresponding 11-hydroxy-compound is oxidized with a solution of chromium trioxide in acetic acid. Thus, when 11 3,17a,21-trihydroxy- 6-fluoro-16a-methyl-4,6-pregnadiene-3,20-dione ZI-acetate is contacted with a solution of chromium trioxide in acetic acid there is formed 17a,21-dihydroxy-6 fiuoro 16amethy-l-4,6-pregnatriene-3,1 1,20-trione 21-acetate.

The selenium dioxide dehydrogenation procedure is conveniently conducted by bringing the 17a,21-dihydroxy- 6 fiuoro l6-methyl 11-oxygenated-4,6-pregnadiene- 3,20-dione 2l-ester, and selenium dioxide together in the presence of an organic solvent such as, for example, dioxane, an alcohol solvent such as t-butanol, etc., and heating the mixture at an elevated temperature. It has been found desirable in conducting this reaction, to have mercury present in the reaction mixture in small amounts, preferably one or two drops, in order to suppress the formation of unwanted by-products. When t-butanol is used as the solvent, it is ordinarily preferred to carry out this reaction at the boiling point of the solvent, under which conditions the reaction is ordinarily complete in about fifteen hours. The reaction mixture is ordinarily filtered, thereby removing metalic selenium, and the filtered solution is evaporated to dryness in vacuo to give the desired 17a,2l-dihydroxy-6-fiuoro-16-methyl- 11-oxygenated-1,4,6-pregnatriene-3,20-dione 2l-ester, such as, for example, 11,8,17u,21-trihydroxy-6-fiuoro-1Got-methyl- 1,4,6 pregnatriene-3,20-dione 2l-acetate, 17a,21-dihydroxy 6 fluoro-16fimethyl-l,4,6-pregnatriene-3,l1,20- trione Zl-acetate, and the like. The crude material obtained in this Way is conveniently purified 'by paper strip chromatography, or if desired, by chromatography using silica gel, activated alumina, and the like. After separation of the dehydrogenated product from unreacted starting material, the product can be purified further, if desired, by recrystallization from a solvent such as ethyl acetate, ethyl acetate-petroleum ether, and the like.

The starting materials which are employed in the process of our invention are 17a,21-dihydroxy-6-fluor0-l6- methyl 11 oxygenated-4-pregnene-3,ZO-dione 21-acylates, and their 9rt-halo derivatives, as for example 17a,2ldihydroxy 60c fluoro-16a-methyl-4-pregnene-3,11,20= trione 21-acetate, 11B,17u,2l-trihydroxy-6u-fluoro-16B- methyl 4 pregnene-3,20-dione 21-tertiary butyl acetate, 6a,9a difluoro ll/3,l7o,2l trihydroxy-16a-methyl-4- pregnene-3,20-dione 2l-acetate and the like, and are prepared in accordance with the disclosure in copending applications Ser. Nos. 746,661 and 746,662, now abandoned, both filed July 7, 1958. Other ZI-acylates, more particularly the 21-lower hydrocarbon acylate such as the 21-benzoate, and other 21-lower alkanoates, such as the 2l-propionate, Zl-tertiary butyl acetate, and the like may likewise be employed. These 2l-propionates and 21-benzoates, as well as the above-mentioned tertiary butyl acetates and other esters, are readily prepared from the corresponding 2l-free alcohol corresponding to the abovementioned 21-acetates by reaction with the appropriate alkanoyl chloride, as for example, propionyl chloride, benzoyl chloride or tertiary 'butyl acetyl chloride in the presence of a tertiary amine base such as pyridine.

When the above enumerated starting materials are subjected to the above dehydrogenation procedures the corresponding 17a,21 dihydroxy-6-fluoro-16-methyl-1l-oxygenated 4,6-pregnadiene-3,20-dione and 1,4,6-pregnatriene compounds are formed, which include 17a,21-dihydroxy 6 fluoro-l6tx-methyl-4,6-pregnadiene-3,11,20- trione 21 acetate, 11,8,l7a,2 l-trihydroxy-6fiuoro-16amethyl 4,6-pregnadiene-3,20-dione Zl-acetate, 6,9oc-difiuoro 11B,l7a,2l trihydroxy-l6fl-methyl-4,6-pregnadiene 3,20 dione 21-propionate, 17a,21-dihydroxy-6- fiuoro 16oz methyl-1,4,6-pregnatriene-3,11,20-trione 21- tertiary butyl acetate, 11fi,17a,21-trihydroxy-6-fiuoro-16B- methyl 1,4,6 pregnatriene-3,20-dione 21-acetate, 6,9adiiluoro 17oc,2l dihydroxy-l6a-methyl-1,4,6-pregnatriene 3,11,20 trione ll-acetate, and the like. These esters may be converted by treatment with potassium bicarbonate in aqueous methanol to produce the 2l-hydroxy compounds corresponding to the above enumerated 21- esters.

This invention also contemplates the Zl-desoxy deriva tives of 17m,21-dihydroxy-6-fiuoro-l6-methyl-1l-oxygenated 4,6-pregnadiene-3,ZO-dione and 17a,2l-dihydroxy-6- fluoro 16-methyl-1l-oxygenated-l,4,6-pregnatriene-3,20- dione compounds, namely, 17u-hydroxy-6-fluoro-16-metl1- yl-ll-oxygenated-4,6-pregnadiene-3,ZO-diones and 17ahydroxy 6-fluoro-16-methyl-ll-oxygenated-l,4,6-pregnatriene-3,20-diones, and 9-halo derivatives thereof, and processes for preparing these compounds.

In carrying out the process for preparing these 21- desoxy derivatives, a lower alkane sulfonyl halide, such as methane-sultonyl chloride, is reacted with 17a,21-dihydroxy 6 fluoro-16-methyl-11-oxygenated4,6-pregnadiene 3,20-dione, 17a,2l-dihydroxy-6-fluoro-l6-methylll oxygenated 1,4,6-pregnatriene-3,ZO-dione, and their 9-halo derivatives. The reaction is conveniently conducted by bringing the reactants together in solution in a tertiary amine such as pyridine and preferably at a temperature of about -5 C., under which conditions the reaction is ordinarily complete in approximately one hour. The reaction mixture is diluted with water, and the material which precipitates is recovered and dried to give the corresponding 1701,21 dihydroxy-6-fiuoro-16methyl-1l-oxygenated- 4,6-pregnadiene-3,20-dione 21-methane sulfonate, 17o ,21- dihydroxy 6-fiuorol6-methyl-11-oxygenated-l,4,6-pregnatriene-3,20-dione 21-rnethane sulfonate, and 9-halo derivatives thereof.

The reaction between the alkali metal iodide such as sodium iodide and 170:,2l-dihydroxy-6-fluoro-l6-methyl- 11 oxygenated 4,6-pregnadiene-3,20-dione 2l-mcthane sulfonate, 17a,21 dihydroxy 6-fluoro-l6-methyl-1 1- oxygenated 1,4,6 pregnatriene-3,20-dione ZI-methane sulfonate, and 9-halo derivatives thereof, is conveniently conducted by bringing the reactants together in an organic solvent medium, for example, an aliphatic ketone such as acetone, and heating the resulting mixture at a temperature of approximately 5060 C., under which conditions the reaction is ordinarily complete in approximately one hour. The reaction mixture is cooled, diluted with water, and the material which precipitates is recovered and dried to give the corresponding 2l-iodo-l7ahydroxy 6 fiuoro-l6-methyl-1l-oxygenated-4,6-pregnadiene-3,20-dione, 21 iodo-17a-hydroxy-6-fluoro-l6-methyl ll oxygenated-1,4,6-pregnatriene-3,ZO-dione, and 9- halo derivatives thereof.

The above-mentioned 2l-iodo-steroid is then reacted with a reducing agent as, for example, hydrogen in the presence of a hydrogenation catalyst such as platinum, nickel, palladium and oxides of these metals, chromous chloride, alkali metal bisulfite, and the like. When hydrogen is used as the reduciug agent, the hydrogenation reaction is ordinarily conducted in a solvent such as an alcohol, for example, ethanol, methanol or propanol. The reaction is carried out at a temperature in the range of 0 C. to C., preferably at room temperature, until one mole of hydrogen is taken up, thereby forming the corresponding 21-desoxy steroid compound. Alternatively, the 2l-iodo-steroid is reacted in an organic solvent such as dioxane with aqueous chromous chloride, preferably in an inert atmosphere while maintaining the reaction mixture at substantially room temperature. The reduction is also conveniently carried out by reacting the 2l-iodo-steroid with an alkali bisulfite in an aqueous organic solvent solution, for example, aqueous ethanol, and preferably at an elevated temperature. The reduced product, the 2l-desoxy steroid, is conveniently recovered by diluting the reaction mixture with Water and extracting the 21-desoxy steroid from the equeous mixture with an organic solvent such as chloroform. The chloroform extracts are washed with water, aqueous alkaline solution, dried and the chloroform solution evaporated to give the 21-desoxy steroid, the hydroxy 6 fluoro l6 methyl-11oxygenated-4,6- pregnadiene-3,20-dione, 17a-hydroxy-6-fiuoro-l6-methyl- 1l-oxygenated-1,4,6-pregnatriene-3,20-dione, and 9-halo derivatives thereof, for example, 17m-hydroxy-6-fiuoro- 16ot-methyl-4,6-pregnadiene-3,11,20-trione, llfl,l7u-dihydroxy 6 fluoro 16B methyl 1,4,6 pregnatriene-3,20- dione 6,9a difluoro-17a-hydroxy-6-fluoro-16a-methyl- 4,6-pregnadiene-3,11,20-trione, and the like.

Alternatively, the 21 iodo 17o: hydroxy-6-fluoro-l6- methyl 11 oxygenated-4,6-pregnadiene-3,20-dione and 1,4,6-pregnatriene compounds and 9-halo derivatives thereof may be reacted with a phosphorylating agent to produce the corresponding 2l-phosphate ester. An inorganic phosphate, as, for example, silver dihydrogen phosphate, or an organic phosphate, preferably a bis-aralkyl ortho-phosphate such as dibenzyl ortho-phosphate and the like, may be employed as the phosphorylating agents. When the latter is employed the reaction is conveniently carried out by bringing together, in an organic solvent for the reactants such as benzene, toluene, xylene or dioxane, a salt of the bis-aralkyl ortho-phosphate and the 21-iodo- 17a hydroxy 6 fluoro 16 methyl-l l-oxygenated- 4,6- pregnadiene-3,20-dione or the corresponding 1,4,6-pregnatriene compound. As the salt of the organic phosphate, it is preferred to use a salt, the cation of which forms insoluble iodides in the organic solvent employed for the reaction, such as silver dibenzyl ortho-phosphate, sodium di benzyl ortho-phosphate, potassium dibenzyl ortho-phosphate, barium dibenzyl ortho-phosphate, calcium dibenzyl ortho-phosphate, and the like. The reaction is conveniently carried out at the reflux temperature of the solvent, under which conditions reaction is ordinarily complete in about 4 to 26 hours.

Alternatively, if silver dihydrogen phosphate is employed as the phosphorylating agent the reaction is carried out by bringing together the 21-iodo steroid with a silver phosphate-phosphoric acid mixture preferably containing about two moles of phosphoric acid per mole of yellow trisilver phosphate. A slight excess of phosphoric acid over this amount is advantageous although an insufliciency is operable. Concentrated phosphoric acid, for example, either 85% or 100%, is preferred as a source of phosphoric acid. This mixture of silver phosphate and phosphoric acid may behave as the equivalent of silver dihydrogen phosphate, AgH PO in the reaction of the present invention. The silver phosphate-phosphoric acid and 21- iodo steroid reagent may be mixed substantially simultaneously at the onset of the reaction. It is also permissible to premix the silver phosphate and phosphoric acid. In practice it is preferable to mix intimately finely divided silver phosphate and the phosphoric acid so as to obtain a good dispersion. The reaction between the l2-iodo steroid and the silver dihydrogen phosphate is conveniently carried out in an inert organic solvent medium. Acetonitrile has been found to be a particularly advantageous solvent, although various other solvents such as diethyl ether, 1,4- dioxane, tetrahydrofuran, acetone, and dimethyl sulfone may also be used. The reaction temperature and time are not critical, although, of course, the reaction time is speeded as the temperature is increased. The reaction may be carried out advantageously at reflux temperature. The reaction time may vary widely. When carrying out the reaction in acetonitrile at reflux temperature, for example, a reaction time of 1% hours has been found sufiicient, and three hours has also been found satisfactory. Shorter and longer reaction times are also permissible.

At the conclusion of the above reactions with either the organic, or inorganic phosphorylating agents, the 21- phosphate derivative is recovered, either as the free acid, i.e., the dihydrogen phosphate acid ester, or as the corresponding mono or dialkali metal salt. Various procedures may be used for recovery. One procedure which has been found quite desirable is to dilute the reaction products with water, remove the organic solvent by vacuum distillation, and thereafter treat the remaining aqueous solution to recover the desired phosphate compound. This may be done, for example, by raising the pH to within the range of 4 to 11, preferably 6 to 10, by the addition of either an alkali metal base such as sodium hydroxide or an alkali metal carbonate such as sodium carbonate. This converts the steroid dihydrogen phosphate acid ester to the corresponding alkali metal salt, and at the same time precipitates excess silver as trisilver phosphate. The insoluble material may be removed by filtration. The steroid phosphate salt may be recovered from aqueous solution by freeze drying and extraction of the anhydrous solid material which remains with a suitable organic solvent such as dry methanol. The methanolic extract of the 2l-phosphate salt may then be obtained as th free acid by acidification with a strong mineral acid or preferably by contact with a cation exchange resin in its hydro-gen form. The use of an ion exchange resin is preferable to the use of common mineral acids so as to avoid contamination by inorganic salts. The 2l-phosphate free acid is eluted and, if desired, concentrated, and then precipitated by the addition of a suitable non-polar liquid, such as diethyl ether or ethyl acetate. The resulting 21- dihydrogen phosphate may be used as such in pharmaceutical formulations, or may be converted to desired salts. Suitable neutralizing agents include sodium hydroxide, sodium methoxide, sodium carbonate, potassium hydroxide, ammonium hydroxide, calcium hydroxide, barium hydroxide and the like. The steroid monosodium phosphates can be formed by neutralization of the free acid to a pH less than 7, and the disodium phosphates can be formed by neutralization to a pH greater than 7, preferably 9 to 10.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given for purposes of illustration and not of limitation.

EXAMPLE 1 A suspension containing mg. of 17a,21-dihydr0xy- 60c fluoro 16a methyl 4 pregnene-3,11,20-trione ZI-acetate, 350 mg. of chloranil, 4.2 ml. of ethyl acetate and 0.9 ml. of acetic acid is refluxed for 17 hours under nitrogen. The reaction mixture is diluted with 20 ml. of ethyl acetate and filtered. The filtrate is Washed sequentially with two 10 ml. portions of ice cold 10% aqueous sodium bisulfite solution, three 10 ml. portions of ice cold 5% aqueous potassium hydroxide solution and finally washed to neutrality with several 10 ml. portions of ice water. The aqueous washes are re-extracted with 25 ml. of ethyl acetate and treated as above. The combined organic phase is dried over sodium sulfate and concentrated in vacuo. The crude material dissolved in benzene is chromatographed on 7.5 g. of acid washed alumina. Elution with chloroforrnzether 2:8 affords 17a,2l-dihy droxy 6 fluoro 16a methyl 4,6 pregnadiene- 3,11,20-trione 21-acetate. This product is then hydrolyzed by treatment with a solution of potassium bicarbonate in aqueous methanol to form 17a,21 dihydroxy 6 fluoro- 16u-methyl-4,6-pregnadiene-3,1 1,20-trione.

In accordance with the above procedure but starting with 17a,21 dihydroxy 60c fluoro 16B methyl-4- pregnene 3,11,20-trione 21-acetate there are obtained 17ot,21 dihydroxy 6 fluoro 16,8 methyl 4,6- pregnadiene-3,11,20-trione and its 2l-acetate.

EXAMPLE 2 A suspension containing 150 mg. of 1l,8,l7ot,2l trihydroxy 6oz fluoro 16a methyl 4 pregnene-3,20- dione 2l-acetate, 350 mg. of chloranil, 4.2 ml. of ethyl acetate and 0.9 ml. of acetic acid is refluxed for 17 hours under nitrogen. The reaction mixture is diluted with 20 ml. of ethyl acetate and filtered. The filtrate is washed sequentially with two 10 ml. portions of ice cold 10% aqueous sodium bisulfite solution, three 10 ml. portions of ice cold 5% aqueous potassium hydroxide solution and finally washed to neutrality with several 10 ml. portions of ice water. The aqueous washes are re-ext-racted with 25 ml. of ethyl acetate and treated as above. The combined organic phase is dried over sodium sulfate and concentrated in vacuo. The crude material dissolved in benzene is chromatographed on 75 g. of acid washed alumina. Elution with chloroformsether 2:8 affords llfi,l7oc,21 trihydroxy 6 fluoro 16cc methyl-4,6- pregnadiene-3,20-dione 21-acetate. This product is then hydrolyzed by treatment with a solution of potassium bicarbonate in aqueous methanol to form l1/3,l7a,2l-trihydroxy 6 fluoro a methyl 4,6-pregnadiene-3,20- dione.

In accordance with the above procedure but starting with 11,8,17oc,21 trihydroxy 6a fluoro 16B methyl- 4-pregnene 3,20 dione 2l-acetate there are obtained 11fl,17a,2l trihydroxy 6 fluoro 16 3 methyl-4,6- pregnadiene-3,20-dione and its 21-acetate.

EXAMPLE 3 A suspension containing 150 mg. of 6u,9a-difluoro-ll5, :,2l-trihydroxy-l6a-methyl-4-pregnane-3,20 dione 21- acetate, 350 mg. of chloranil, 4.2 ml. of ethyl acetate and 0.9 ml. of acetic acid is refluxed for 17 hours under nitrogen. The reaction mixture is diluted with 20 m1. of ethyl acetate and filtered. The filtrate is washed sequentially with two 10 ml. portions of ice cold 10% aqueous sodium bisulfite solution, three 10 ml. portions of ice cold 10% aqueous sodium bisulfite solution, three 10 ml. portions of ice cold 5% aqueous potassium hydroxide solution and finally washed to neutrality with several 10 ml. portions of ice water. The aqueous washes are reextracted with 25 ml. of ethyl acetate and treated as above. The combined organic phase is dried over sodium sulfate and concentrated in vacuo. The crude material dissolved in benzene is chromatographed on 7.5 g. of acid washed alumina. Elution with chloroformzether 2:8 affords 6,9x-difiuoro-1lfi,l7a,2l-trihydroxy-16a-methyl-4,6- pregnadiene-3,20-dione 21-acetate. This product is then hydrolyzed by treatment with a solution of potassium bicarbonate in aqueous methanol to form 6,90L-dlfillOI'O- 1l5,17ot,2l-trihydroxy-l6a-methyl-4,6-pregnadiene 3,20- dione.

Similarly, in accordance with the above procedure but starting with 6a,9a-difluoro-1113,17a,21-trihydroxy-16/imethyl-4-pregnene-3,20-dione Zl-acetate, there is obtained the corresponding 6,9u-difi'uoro-11fl,17a,2l-trihydroxy- 16ti-methyl-4,6-pregnadiene-3,20-dione and its 2l-acetate.

EXAMPLE 4 A suspension containing 150 mg. of 60:,9wd1fi1101'0-17a, 21 dihydroxy-16a-methyl-4-pregnene-3,11,20-trione 21- acetate, 350 mg. of chloranil, 4.2 ml. of ethyl acetate and 0.9 ml. of acetic acid is refluxed for 17 hours under nitrogen. The reaction mixture is diluted With 20 ml. of ethyl acetate and filtered. The filtrate is washed sequentially with two 10 ml. portions of ice cold 10% aqueous sodium bisulfite solution, three 10 ml. portions of ice cold 5% aqueous potassium hydroxide solution and finally washed to neutrality with several ml. portions of ice water. The aqueous washes are re-extracted with 25 ml. of ethyl acetate and treated as above. The combined organic phase is dried over sodium sulfate and concentrated in vacuo. The crude material dissolved in benzene is chromatographed on 7.5 g. of acid washed alumina. Elution with chloroformzether 2:8 affords 6,9a-difiuoro-17a,21-dihydroxy-16a-methyl-4,6preguadiene-3,11,20 trione 2l-acetate. This product is then hydrolyzed by treatment with a solution of potassium bicarbonate in aqueous methanol to form 6,9 difluoro 17u,21-dihydroxy-16a-methyl-4,6- pregnadiene-3,11,20-trione.

EXAMPLE 5 To a solution of 100 mg. of 17a,2l-dihydroxy-6-fluoro- 16u-methyl-4,6-pregnadiene-3,11,20-trione 21-acetate in 0.10 ml. of acetic acid and 6 ml. of t-amyl alcohol is added 60 mg. of selenium dioxide and 1 drop of mercury. The mixture is refluxed under nitrogen overnight. The solution is filtered, washed with sodium bicarbonate, dried, and concentrated. This product is chromatographed on acid washed alumina. The adsorbate is eluted with mixtures of chloroform and ether, increasingly rich in chloroform. The eluates are combined, evaporated to dryness and the residual material recrystallized from ethyl acetate to give 17a,21-dihydroxy-6-fluoro-16a-methyl-1,4,6-pregnatriene-3,11,20-trione 2l-acetate. This product is then hydrolyzed by treatment with a solution of potassium bicarbonate in aqueous methanol to form 17a,21-dihydroxyfluoro-16a-metl1yl-1,4-6-pregnatriene-3,1 1,20-tn'one.

In accordance with the above procedure but starting with 1711,21 dihydroxy-6-fiuoro-16B-methyl-4,6-pregnadiene-3,11,20-trione 21-acetate there are obtained 17oz,- 21-dihydroxy-6-luoro-16B-methy1- 1,4,6 pregnatriene-3,- 11,20-trione and its Ill-acetate.

EXAMPLE 6 To a solution of 100 mg. of 11B,17a,21-trihydroxy-6- fiuoro-l6a-methyl-4,6-pregnadiene-3,20 dione 21-acetate in 0.10 ml. of acetic acid and 6 ml. of t-amyl alcohol is added 60 mg. of selenium dioxide and 1 drop of mercury. The mixture is refluxed under nitrogen overnight. The solution is filtered, washed with sodium bicarbonate, dried, and concentrated. This product is chromatographed on acid-washed alumina. The adsorbate is eluted with mixtures of chloroform and ether, increasingly rich in chloroform. The eluates are combined, evaporated to dryness and the residual material recrystallized from ethyl acetate to give llB,17a,21-trihydroxy-6-fluoro-l6ct-methyl- 1,4,6-pregnatriene-3,ZO-dione 21-acetate. This product is then hydrolyzed by treatment with a solution of potassium bicarbonate in aqueous methanol to form 1l(3,17a,21-trihydroxy-6*fluoro-16a-methyl-1,4,6-pregnatriene 3,20-dione.

In accordance with the above procedure but starting with 11B,17a,21-trihydroxy-6-fluoro-16fi-methyl-4,6-pregnadiene-3,20-dione 2l-acetate there are obtained 11 {3,17 21-trihydroxy-6-fiuoro-16p-methyl-1,4,6-pregnatriene 3,- ZO-dione and its 21-acetate.

EXAMPLE 7 To a solution of mg. of 6,9oc-difltl0r0-llfl,l7oc,2ltrihydroxy-l6u-methyl-4,6-pregnadiene-3,20-dione 21-acetate in 0.10 ml. of acetic acid and 6 ml. of t-arnyl alcohol is added 6.0 mg. of selenium dioxide and 1 drop of mercury. The mixture is refluxed under nitrogen overnight. The solution is filtered, washed with sodium bicarbonate, dried and concentrated. This product is chromatographed on acid washed alumina. The adsorbate is eluted with mixtures of chloroform and ether, increasingly rich in chloroform. The eluates are combined, evaporated to dryness and the residual material recrystallized from ethyl acetate to give 6,9u-difiuoro-l1,8,1711,21-trihydroxy-16a-methyl- 1,4,6-pregnatriene-3,20-dione 21-acetate. This product is then hydrolyzed by treatment with a solution of potassium bicarbonate in aqueous methanol to form 6,9a-difiuoro- 11b,17a,21-trihydroxy-1oa-methyl-1,4,6-pregnatriene 3,- 20-dione.

In accordance with the above procedure but starting with 6,9a-difiuoro-l113,17a,2l-trihydroxy-16t3-methyl-4,6- pregnadiene-3,20-dione 21-acetate there are obtained 6,90:- difluoro llfi,l7a,21 trihydroxy 165 methyl 1,4,6- pregnatriene-"J,20-dione and its 21-acetate.

EXAMPLE 8 To a solution of 100 mg. of 6,9ot-difiuoro-17a,21-dihydroxy 16cc methyl-4,6-pregnadiene-3,11,20-trione 2lacetate in 0.10 ml. of acetic acid and 6 ml. of t-amyl alcohol is added 60 mg. of selenium dioxide and 1 drop of mercury. The mixture is refluxed under nitrogen overnight. The solution is filtered, washed with sodium bicarbonate, dried, and concentrated. This product is chromatographed on acid-Washed alumina. The adsorbate is eluted with mixtures of chloroform and ether, increasingly rich in chloroform. The eluates are combined, evaporated to dryness and the residual material recrystallized from ethyl acetate to give 6,9u-difluoro-17a,21-dihydroxy 16oz methyl 1,4,6-pregnatriene-3,11,20-trione 21-acetate. This product is then hydrolyzed by treatment with a solution of potassium bicarbonate in aqueous methanol to form, 6,9oc-CliflUOIO-17a,21dil1ydI'OXy-160tmethyl-1,4,6-pregnatriene-3 ,11,20-trione.

In accordance with the above procedure, but starting with 6,9a difiuoro l7oc,2l dihydroxy-l6fl-rnethyl4,6- pregnadiene-3,l1-20-trione 21-acetate there are obtained 6,90: difiuoro 17a,21 dihydroxy-l6/3-methyl-1,4,6- pregnatriene-3,11,20-trione and its 21-acetate.

EXAMPLE 9 To a solution of 43 mg. of 17a,2ldihydroxy-6-fiuoro- 16u-methyl-4,6-pregnadiene-3,11,20-trione, in 0.3 ml. of pyridine, cooled to 0 C., is added 0.02 ml. of methanesulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period at approximately 1 hour. Water is then added to the reaction mixture and the crystalline precipitate which forms is recovered, washed with water, and dried to give 1711,21- dihydroxy 6 fiuoro 16a methyl 4,6 pregnadiene- 3,11,20-trione 21-methane sulfonate.

To 90 mg. of 17a,21-dihydroxy-6-fluoro-16a-methyl- 4,6-pregnadiene-3,11,20-t1'ione 2l-methane sulfonate dis solved in 5 ml. of actone is added mg. of sodium iodide. The resulting mixture is heated at reflux temperaature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The crystalline material which precipitates is recovered, Washed with water, and dried to give 21-iodo- 17a hydroxy 6 fluoro 16a-methyl-4,6-pregnadiene- 3,11,20-trione.

This 21 iodo 17a-hydroxy-6-fiuoro-16a-methyl-4,6- pregnadiene-3,11,20-trione is dissolved in a mixture of 2.5 ml. of Water and 2.5 ml. of ethanol. T o the resulting suspension is added 250 mg. of sodium bisulfite and the mixture is heated under reflux for a period of about 1 hour. The reaction solution is cooled, diluted with Water, and the crystalline material which separates is recovered, washed with water, dried and recrytallized from ethyl acetate to give l7a-hydroxy-6-fluoro-16a-methyl-4,6- pregnadiene-3 l 1,20-trione.

In accordance with the above procedures but starting with 170:,21 dihydroxy 6-fluoro 16B methyl-4,6- pregnadiene-3,l1,20-trione there is obtained, following the reaction with methane-sulfonyl chloride, 17a,21-dihydroxy 6 fluoro-16B-methyl-4.6-pregnadiene-3,11,20- trione 21-methane sulfonate which upon reaction with sodium iodide in acetone is converted to 21-iOd0-l7ochydroxy 6 fluoro 16/i-methyl-4,6-pregnadiene-3,l1,20- trione, which upon reaction with sodium bisulfite is converted to 1700 hydroxy 6 fluoro 16p methyl 4,6- pregnadiene-3,l1,20-trione.

EXAMPLE 10 To a solution of 43 mg. of 11fi,l7u,21-trihydroxy-6- fluoro-16ot-methyl-4,6-pregnadiene-3,20-dione in 0.3 m1. of pyridine, cooled to C., is added 0.02 ml. of methanesulfonyl chloride. The resulting mixture is allowed to stand at a temperature of approximately 0 C. for a period of approximately 1 hour. Water is then added to the reaction mixture and the crystalline precipitate which forms is recovered, washed with water, and dried to give 1lfi,l7oc 21 trihydroxy-6-fluoro 16oz methyl 4,6- prcgnadiene-3,20-dione 21methane sulfonate.

To 90 mg. of 11,8,17u,21-trihydroxy-6-fiuoro-16amethyl-4,6-pregnadiene-3,20-dione 21-methane sulfonate dissolved in ml. of acetone is added 150 mg. of sodium iodide. The resulting mixture is heated at reflux temperature for a period of approximately 1 hour, and the reaction solution is cooled to room temperature and diluted with water. The crystalline material which precipitates is recovered, washed with Water, and dried to give 21- iodo 11 6,1704 dihydroxy 6 fluoro-16a-methyl-4,6- pregnadiene-3,20-dione.

160 mg. of trisilver phosphate are thoroughly mixed with 0.1 ml. of 100% phosphoric acid, and the silver dihydrogen phosphate thus obtained is Washed by decantation with two portions of diethyl ether to remove unreacted phosphoric acid. Approximately 1.0 ml. of acetonitrile are added, and the mixture is heated to reflux temperature. To the resulting mixture are then added 21-iodo-11 3,171 dihydroxy 6 fluoro 16a-methyl-4,6-pregnadiene-3,20- dione, and the mixture is heated under reflux in a nitrogen atmosphere with stirring for a period of approximately 75 minutes. The reaction mixture is cooled to room temperature, about 1.0 g. of ice water is added, and the acetonitrile is evaporated in vacuo at a temperature below about 25 60 C. The pH of the resulting aqueous suspension is adjusted to 6.4 by the addition of 0.12 ml. of saturated 10 aqueous sodium carbonate solution. The precipitate, which forms, is removed by filtration and washed thoroughly with water. The filtered aqueous solution and Washes are combined, and dried from the frozen state, and the residual material is triturated with seven 0.5 ml. portions of methanol. The methanol-insoluble material is separated by filtration, the filtered methanolic solution is evaporated in vacuo to a volume of approximately 0.1 ml., and 1.0 ml. of ether are added to the concentrated methanolic solution. The material which precipitates is recovered, washed with ether, and dried to give 11,8,l7a,21-trihydroxy 6 fluoro 16a methyl-4,6-pregnadiene-3,20- dione 2l-dihydrogen phosphate.

In accordance with the above procedures but starting with 1lfi,17a,21 trihydroxy 6 fluoro 16f? methyl- 4,6 pregnadiene 3,20 dione there is obtained, following the reaction with methanesulfonyl chloride, 1113,1711, 21 trihydroxy 6 fluoro methyl 4,6 pregnadiene 3,20 dione 21 methane sulfonate, which upon reaction with sodium iodide in acetone is converted to 21 iodo 1lfl,17oc dihydroxy 6 fluoro 16B methyl- 4,6 pregnadiene 3,20 dione, which, upon reaction with a mixture of silver phosphate and phosphoric acid, is converted to 113,17 dihydroxy 6 fluoro 16p methyl 4,6 pregnadiene 3,20 dione 21 dihydrogen phosphate.

Various changes and modifications may be made in the present invention, certain preferred embodiments of which are herein disclosed, without departing from the scope thereof; to the extent that these changes and modifications are within the scope of the appended claims, they are to be considered a part of this invention.

1 claim:

1. 11fl,17u,21 trihydroxy 6 fluoro 16a methyl 4,6-pregnadiene-3,20-'dione.

2. 1lB,17a,21 trihydroxy 6 fluoro 16a methyl 4,6 pregnadiene 3,20 dione 21 phosphate.

3. ll,6,l7oc,2l trihydroxy 6 fluoro 16a. methyl 4,6 pregnadiene 3,20 dione 21 phosphate.

4. 11B,17oc,21 trihydroxy 6 fluoro 16cc methyl 4,6 pregnadiene 3,20 dione 21 (tertiary butyl ace tate).

5. 11fl,17a,21 trihydroxy 6 fluoro 16a methyl 1,4,6 pregnatriene 3,20 dione.

6. 11,8,17a,21 trihydroxy 6 fluoro 16oz methyl 1,4,6 pregnatriene 3,20 dione 21 phosphate.

7. 11/3,17a,21 trihydroxy 6 fluoro 16cc methyl 1,4,6 pregnatriene 3,20 dione 21 (tertiary butyl acetate).

References Cited UNITED STATES PATENTS 2,838,536 6/1958 Magerlein et al. 260397.45 2,877,239 3/ 1959 Angello et a1 260 -3914 2,936,313 5/1960 Elks et al. 260397.45 2,963,498 12/1960 Bergstrom et a1. 260397.45 2,997,489 8/1961 Ringold et a1. 260-397.45

LEWIS GOTTS, Primary Examiner.

L. H. GASTON, M. LIEBMAN, Examiners. G. E. LANDE, H. FRENCH, Assistant Examiners. 

1. 11B,17A,21-TRIHYDROXY-6-FLUORI-16A-METHYL4,6-PREGNADIENE-3,20-DIONE. 